端锚聚合酶（Tankyrase）属于聚腺苷二磷酸核糖聚合酶（PARP）家族，主要通过聚腺苷二磷酸核糖基化而对特定蛋白质及自身进行翻译后修饰。近年来，随着Tankyrase在维持端粒长度、调节Wnt信号通路、调节细胞有丝分裂、影响颌骨增大症及调节胰岛素刺激的葡萄糖吸收等相关功能的不断发现，Tankyrase已成为越来越热的潜在性抗肿瘤靶标，其抑制剂有望成为抑癌基因BRCA缺失或Wnt/β-catenin信号通路失调所引起的肿瘤治疗候选药物。本项目拟靶向Tankyrase的催化结构域和识别被修饰蛋白质的ARC结构域，主要采用基于片段的先导化合物发现方法，设计与发现结构新颖、选择性高和抑制效率强的Tankyrase抑制剂。

Tankyrases belong to the poly(ADP-ribose) polymerase (PARP) protein superfamily, which catalyze the post-translational modification of proteins using β-NAD+ as a substrate to successively add ADP-ribose moieties onto target proteins or themselves. Tankyrases play roles in regulating a variety of cellular processes, including maintenance of the telomere length, regulation of the Wnt/β-catenin signal pathway, control of the mitotic chekpoint, and mediation of insulin-stimulated glucose uptake. The highlight of these functions makes tankyrases as attractive targets for cancer therapy. Inhibitors of tankyrases have been indicated to be a drug candidate against the cancers induced by BRCA-deficiency or deregulation of Wnt/β-catenin signaling . Here, targeting to both the catalytic and ARC domains of tankyrases, the fragment-based lead discovery (FBLD) will be mainly used to design and discovery novel, highly selective, and potent inhibitors for tankyrases.